17-43091435-C-A

Position:

• chr17-43091435-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_007294.4(BRCA1):​c.4096G>T​(p.Gly1366Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1366D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.73

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a compositionally_biased_region Polar residues (size 33) in uniprot entity BRCA1_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43091032-C-T is described in Lovd as [Pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4096G>T	p.Gly1366Cys	missense_variant, splice_region_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4096G>T	p.Gly1366Cys	missense_variant, splice_region_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.1	M;M;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.029	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.98	D;.;.;D
Vest4		0.52
MutPred		0.13		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);
MVP		0.95
MPC		0.47
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.15
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.68		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs431825405; hg19: chr17-41243452;